Kawasaki disease in neonates: a case report and literature review

Background Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology that affects infants and young children but is extremely rare in neonates, especially afebrile KD. We present a case of KD without fever in a neonate and review the literature on KD in neonates. Case presentation A newborn female was hospitalized because her peripheral blood leukocytes increased for half a day. The admission diagnosis was considered neonatal sepsis and bacterial meningitis. She had no fever since the admission, but a rash appeared on her face by the 7th day. On day 11 after admission, there was a desquamation on the distal extremities. On day 15 after admission, ultrasound showed non-suppurative cervical lymphadenopathy. Echocardiogram revealed coronary artery aneurysms in both sides. Finally, the patient was diagnosed with incomplete KD (IKD). The follow-up echocardiogram showed that the internal diameter of both coronary arteries returned to normal three months after birth. Conclusions Fever, rash, and distal extremity desquamation during the recovery phase are the most common symptoms of IKD. When newborns present with clinical manifestations such as rash, distal extremity desquamation and cervical lymph adenitis and with an increased peripheral blood leukocyte count and progressive increase in platelets simultaneously, the medical staff should be highly alert to the possibility of KD even without fever. The echocardiogram needs to be performed promptly. The incidence of coronary artery lesions is significantly higher if neonatal KD patients miss timely diagnosis and treatment.


Case presentation
A 19-hour-old female patient was transferred to the pediatric ward of China-Japan Friendship Hospital because her peripheral blood leukocytes increased for half a day.She was G1P1, at a gestational age of 40 weeks + 2days, and delivered by cesarean section due to acute intrauterine distress with III-degree contaminated amniotic fluid and slowed fetal heart rate.The Apgar score was 10-point at 1, 5, and 10 min after birth, respectively.The birth weight was 3386 g.The child had no fever, no irritability with a high-pitched cry, no convulsions, and no groans or vomiting after admission.Her temperature was 36.5 ℃, pulse 140/minute, respiration 40/minute, BP 80/55 mmHg, capillary refill less than two seconds.The face and trunk were light yellow.The bregma was bulged and the pressure was slightly higher.The neck resistance was suspiciously positive.The muscular tension in the limbs was normal, and the primitive reflexes were derived.
Meropenem and vancomycin were given to control the infection.Mannitol was used to lower the intracranial pressure, and dexamethasone was used to prevent adhesions.On day 2 of hospitalization, intravenous immunoglobulin (IVIG) was used for three days (total dose 2 g/ kg) as supportive therapy.
The patient had no fever since admission, but a rash appeared on her face by the 7th day and lasted for five days.The PLT reached from 603 × 10 9 /L on day 7 to 1345 × 10 9 /L on day 12 (Table 1).Distal extremity desquamation began on day 11 and continued for ten days (Fig. 1).However, other manifestations including conjunctivitis, erythematous dry lips, red raspberry tongue and swollen extremities did not appeared.Low molecular dextran was given to reduce blood viscosity, enoxaparin sodium was given for anticoagulation, and dipyridamole and low-dose aspirin (5 mg/kg) were administered for anti-platelet aggregation.On the 15th day of the illness, ultrasound showed non-suppurative cervical lymphadenopathy.Echocardiogram showed that the internal diameter of the proximal segment of the left main coronary artery (LMCA) was 5.9 mm (Z = 11.40), the internal diameter of the left anterior descending coronary artery (LAD) was 2.4 mm (Z = 5.19) and the internal diameter of the right coronary artery (RCA) was 3.1 mm (Z = 8.07) (Fig. 2).Electrocardiogram was normal.Moreover, no abnormal blood flow was found in the arteries of the upper and lower extremities.No thrombus was found in the deep veins.Finally, the patient was diagnosed with IKD.Low-dose aspirin and dipyridamole were given to prevent platelet aggregation continuously.On 21 days after admission, the blood analyses showed WBC was 10.17 × 10 9 /L (neutrophils was 17.2%, lymphocytes was 61.2%, monocytes was 12.1%), RBC was 2.69 × 10 12 /L, hemoglobin was 90 g/L, PLT was 499 × 10 9 /L, and CRP was < The patient was discharged with low-dose aspirin and dipyridamole after 21 days in the hospital.Regular follow-up was carried out every 2-4 weeks after discharge.Echocardiogram revealed LMCA of 2.0 mm (Z = 1.69) and RCA of 1.7 mm (Z = 1.78) three months after birth (Table 2).

Discussion
KD is an acute febrile condition seen in children.The diagnostic criteria for KD are fever, bilateral bulbar conjunctival injection, changes in the lips and oral cavity, rash, changes in the peripheral extremities, and nonsuppurative cervical lymphadenopathy.Fever is no longer necessary for the diagnosis of KD, according to the sixth revised edition of the Japanese diagnostic criteria [3].Statistically, neonates with KD have a higher risk of incomplete presentation than older children [2].
There were four patients with no fever among the 19 neonatal KD cases in our literature review.Only one afebrile patient was diagnosed as IKD purely based on CALs [11].The other three afebrile patients [9][10], including the present case, had the same clinical manifestations, such as rash and periungual desquamation.In addition to the above-mentioned manifestations, conjunctival congestion, changes in the lips, and extremity edema were also observed in cases 6 and 7 [9][10] (Table 3).
The immune system of newborns is in a special developmental stage, which might lead to heterogeneity in neonatal KD and explain the higher incidence of IKD in neonates than older children.In this case, the patient did not have fever and other clinical manifestations, such as bilateral bulbar conjunctival injection, changes in the lips and oral cavity, probably associated with the early stage of neonate and the impact of early use of IVIG and dexamethasone.
To date, the etiology of KD is not clear.Previous studies suggested that KD is triggered by an infectious agent based on its occurrence in epidemiological clusters, seasonal variation, and a very low risk of recurrence [19].Other research suggested that neonatal KD could be associated with sepsis and pneumonia [20,21].Although the patient's blood culture and cerebrospinal fluid were all sterile, the infection could not be excluded since abnormally elevated WBC and III-degree contaminated amniotic fluid at birth.We could not distinguish exactly whether this case was a KD secondary to systemic infection or just a KD case from the beginning.
CALs are the primary serious complication affecting the prognosis of KD.Several studies suggested that infants under the age of 6 months not only present more commonly with IKD, but are also at higher risk for coronary artery abnormalities and death [8].In the 19 cases of neonatal KD mentioned above, CALs occurred in 89.5% in 19 neonates and 75% in the four cases of afebrile neonatal KD. 61.1% (11/18) of the patients with CALs had a favorable prognosis after using IVIG.Although this patient initially presented with medium to large coronary aneurysms, the internal diameter of the coronary arteries returned to normal after three months by IVIG treatment on 2nd day after birth.The 24th Nationwide Surveillance in Japan reported that approximately 9%, 25%, and 35% of KD patients received the first IVIG treatment on the 3rd, 4th, and 5th days of illness, respectively, and the prevalence of CALs were lower than before [3].Consistent with this finding, our case suggests that early use of IVIG might be beneficial for long-term prognosis in KD.

Conclusions
This case report and review of the literature suggest a relatively higher incidence of IKD in neonates.Therefore, when newborns present with rash, terminal changes in the extremities or cervical lymph adenitis, increased peripheral blood leukocyte count and CRP, or progressive increase in platelets, the medical staff should be highly alert to the possibility of KD even without fever.Echocardiogram needs to be performed promptly.The incidence of CALs in neonatal KD is significantly higher.

Table 2
Coronary artery parameters of the patient

Table 3
Summary of the case reports of neonatal Kawasaki disease